Protein Kinase C (PKC)ζ Pseudosubstrate Inhibitor Peptide Promiscuously Binds PKC Family Isoforms and Disrupts Conventional PKC Targeting and Translocation.

PKMζ is generated via an alternative transcriptional start site in the atypical protein kinase C isoform, which removes N-terminal regulatory elements, including the inhibitory pseudosubstrate domain, consequently rendering the kinase constitutively active. Persistent PKMζ activity has been proposed as a molecular mechanism for the long-term maintenance of synaptic plasticity underlying some forms of memory. Many studies supporting a role for PKMζ in synaptic plasticity and memory have relied on the pseudosubstrate-derived ζ-inhibitory peptide (ZIP). However, recent studies have demonstrated that ZIP-induced impairments to synaptic plasticity and memory occur even in the absence of suggesting that ZIP exerts its actions via additional cellular targets. In this study, we demonstrated that ZIP interacts with conventional and novel in addition to atypical isoforms. Moreover, when brain abundance of each duanyu1531 isoform and affinity for ZIP are taken into account, the signaling capacity of ZIP-responsive pools of conventional and novel may match or exceed that for atypical Pseudosubstrate-derived peptides, like ZIP, are thought to exert their cellular action primarily by inhibiting duanyu1531 catalytic activity; however, the ZIP-sensitive catalytic core of duanyu1531 is known to participate in the enzyme's subcellular targeting, suggesting an additional mode of ZIP action. Indeed, we have demonstrated that ZIP potently disrupts interaction with the protein A-kinase anchoring protein (AKAP) 79 and interferes with ionomycin-induced translocation of conventional duanyu1531 to the plasma membrane. Thus, ZIP exhibits broad-spectrum action toward the duanyu1531 family of enzymes, and this action may contribute to its unique ability to impair memory.

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